Assessing Longitudinal Treatment Efficacies and Alterations in Molecular Markers Associated with Glutamatergic Signaling and Immune Checkpoint Inhibitors in a Spontaneous Melanoma Mouse Model.

Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.

A Spontaneous Melanoma Mouse Model Applicable for a Longitudinal Chemotherapy and Immunotherapy Study.

Mouse models that reflect human disorders provide invaluable tools for the translation of basic science discoveries to clinical therapies. However, many of these in vivo therapeutic studies are short term and do not accurately mimic patient conditions. In this study, we used a fully immunocompetent, transgenic mouse model, TGS, in which the spontaneous development of metastatic melanoma is driven by the ectopic expression of a normal neuronal receptor, mGluR1, as a model to assess longitudinal treatment response (up to 8 months) with an inhibitor of glutamatergic signaling, troriluzole, which is a prodrug of riluzole, plus an antibody against PD-1, an immune checkpoint inhibitor.

Inhibitors of Keap1-Nrf2 protein-protein interaction reduce estrogen responsive gene expression and oxidative stress in estrogen receptor-positive breast cancer.

Estrogen contributes to the development of breast cancer through estrogen receptor (ER) signaling and by generating genotoxic metabolites that cause oxidative DNA damage. To protect against oxidative stress, cells activate nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream cytoprotective genes that initiate antioxidant responses and detoxify xenobiotics. Nrf2 activation occurs by inhibiting the protein-protein interaction (PPI) between Nrf2 and its inhibitor Keap1, which otherwise targets Nrf2 for ubiquitination and destruction.

Breast cancer stem cells: A review of their characteristics and the agents that affect them.

The evolving concept that cancer stem cells (CSCs) are the driving element in cancer development, evolution and heterogeneity, has overridden the previous model of a tumor consisting of cells all with similar sequentially acquired mutations and a similar potential for renewal, invasion and metastasis. This paradigm shift has focused attention on therapeutically targeting CSCs directly as a means of eradicating the disease. In breast cancers, CSCs can be identified by cell surface markers and are characterized by their ability to self-renew and differentiate, resist chemotherapy and radiation, and initiate new tumors upon serial transplantation in xenografted mice.

Analysis of the Transcriptome: Regulation of Cancer Stemness in Breast Ductal Carcinoma by Vitamin D Compounds.

Ductal carcinoma (DCIS), which accounts for one out of every five new breast cancer diagnoses, will progress to potentially lethal invasive ductal carcinoma (IDC) in about 50% of cases. Vitamin D compounds have been shown to inhibit progression to IDC in the MCF10DCIS model. This inhibition appears to involve a reduction in the cancer stem cell-like population in MCF10DCIS tumors.

Tocopherols inhibit estrogen-induced cancer stemness and OCT4 signaling in breast cancer.

Estrogen plays an important role in breast cancer development. While the mechanism of the estrogen effects is not fully elucidated, one possible route is by increasing the stem cell-like properties in the tumors. Tocopherols are known to reduce breast cancer development and progression.

Revealing the mechanism of tissue damage due to tobacco use: finally, a smoking gun?

This commentary highlights the article by Li et al that presents a compelling case for a mechanism by which tobacco smoke extract (TSE) induces damage to the extracellular matrix, a key element in the pathogenesis of tobacco-related disease.

Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts.

Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I.

Influence of lactoferrin feeding and injection against systemic staphylococcal infections in mice.

Human and bovine lactoferrins (Lfs) and bovine lactoferrin hydrolysate (LH) were assessed in vitro and in vivo for their antibacterial effects on Staphylococcus aureus. Lactoferrins showed weak in vitro antibacterial activity while Fe-saturated Lfs and LH showed no activity. Lactoferrin-treated mice (1 mg, i.

Induction of lactoferrin expression in murine ES cells by retinoic acid and estrogen.

Lactoferrin is an iron-binding glycoprotein present in high concentrations in milk and exocrine fluids such as bile and tears. Many functions have been attributed to lactoferrin, including antimicrobial and antiviral activities, immunomodulation, and cell growth regulation. Lactoferrin expression is controlled by different regulators, including retinoic acid and estrogen.

Biologic activity of interleukin 1 (IL-1) alpha in patients with refractory malignancies.

Interleukin 1 alpha (IL-1 alpha) is a cytokine with pleiotropic effects, including cytotoxic-cytostatic activity against some tumor cell lines. We have conducted a phase I study of recombinant human IL-1 alpha (rhIL-1 alpha) in 17 patients with refractory malignancies to examine its toxicity and biologic activity. rhIL-1 alpha was given as a 2-h IV infusion daily for 5 days at five dose levels (0.

Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer.

To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3.

The effect of continuous infusion IL-1 alpha on carboplatin-induced thrombocytopenia and anti-tumor activity in RIF-1 tumor bearing mice.

Interleukin-1 alpha (IL-1 alpha) has potent effects on hematopoiesis and can significantly enhance the anti-tumor activity of cytotoxic drugs. Studies were undertaken here to determine whether IL-1 alpha, administered by continuous infusion, could prevent carboplatin (CBDCA)-mediated thrombocytopenia and enhance CBDCA-mediated anti-tumor effects. RIF-1 tumor bearing mice were treated with CBDCA and IL-1 alpha either by a single bolus injection or by continuous infusion through the use of ALZET pumps.

Effect of high-dose, fractionated local irradiation on MNU-induced carcinogenesis in the rat mammary gland.

The effect on chemical carcinogenesis in the mammary gland of high-dose fractionated, local irradiation, as is used in the treatment of human breast cancer, was examined in a rat model of this disease process. For this purpose, a highly reproducible method was employed for administering a therapeutic dose and fractionation schedule via an anterior portal to a single mammary gland chain of rats in a manner that minimized whole body irradiation. This approach offers significant advantages over whole body irradiation techniques previously used for investigations of radiation-mediated effects on the carcinogenic process.

Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA.

Lactoferrin, an iron-binding glycoprotein found in high concentrations in human milk and other epithelial secretions and in the secondary (specific) granules of neutrophils, is thought to be responsible for primary defence against microbial infection, mainly as a result of lactoferrin sequestration of iron required for microbial growth. Many other functions have been attributed to lactoferrin, including immunomodulation and cell growth regulation (reviewed in ref. 4).

Potentiation by interleukin 1 alpha of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model.

We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) significantly potentiates the antitumor activity of a variety of chemotherapeutic agents, including cisplatin (cDDP). In studies described here, we examined the potential of combining IL-1 alpha and the platinum analogue carboplatin (CBDCA) and compared the schedule-dependent and pharmacokinetic effects for IL-1 alpha combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.

Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice.

The antitumor effects of the multifunctional iron-binding glycoprotein, lactoferrin (Lf), were investigated. Lf inhibited growth in mice of transplantable solid tumors induced by v-ras transformed fibroblasts and a methylcholanthrene-induced fibrosarcoma. Lf also substantially reduced lung colonization (experimental metastasis) by B16-F10 melanoma cells in syngeneic mice.

Iron-induced conformational change in human lactoferrin: demonstration by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analysis of effects of iron binding to the N and C lobes of the molecule.

Analysis of Fe-saturated- and apo-lactoferrin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) without heating the samples prior to application revealed a substantial difference in mobility. The mobility shift was fully reversible on repetitive removal and readdition of Fe. Binding of a single Fe to the N-lobe binding site was sufficient to cause the gel shift; binding of a second Fe to the C-lobe site did not further alter mobility.

Analysis of the antimetastatic effects of synthetic muramyl tripeptide (CGP 19835A) encapsulated in liposomes in combination with other immunomodulatory agents and chemotherapeutic drugs.

The synthetic molecule muramyl tripeptide (CGP 19835A) encapsulated in liposomes is effective in increasing the survival of mice with spontaneous experimental lung metastases induced by the RENCA renal adenocarcinoma and B16 melanoma tumor models. The present study was aimed at extending the effects of CGP 19835A to another highly metastatic carcinoma model and at evaluating the efficacy of combination therapy with standard cytotoxic agents and other immunomodulators. C57BL/6 mice received whole tumor implants of PancO2, a spontaneously metastasizing pancreatic adenocarcinoma, subcutaneously in the hind leg.

Iron binding to human lactoferrin alters reactivity of the protein with plant lectins.

Binding of Fe by human apolactoferrin results in altered reactivity of the glycoprotein with plant lectins. Reaction with wheat germ agglutinin (WGA) and peanut agglutinin (PNA) was abolished with Fe binding. Reaction with the lectins from Datura stramonium (DSA) and Aleuria aurantia (AAA) was significantly reduced but not fully abolished on Fe binding, while reaction with the Artocarpus integrifolia lectin (Jacalin) and Sambucus nigrabark (SNA) was not changed at all.

Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 monoclonal antibody: phase I study.

Pharmacokinetics of radiolabeled BrE3 monoclonal antibody (Mab), reactive against a breast mucin epitope, were assessed in 15 patients with advanced breast cancer. Patients received 5 mCi (185 MBq) of 111In-methyl benzyl isothiocyanate DTPA (MX-DTPA) conjugated BrE-3 Mab intravenously with total antibody doses of 10, 50 or 100 mg. Serial quantitative imaging, blood and urine clearance were obtained to measure pharmacokinetics, assess tumor localization and estimate radiation dose.

Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma.

Purpose: Tamoxifen is currently advocated for post-menopausal breast cancer patients receiving definitive irradiation after limited surgery. The purpose of this study was to assess in an experimental model for breast cancer whether the efficacy of irradiation is altered by conjoint administration of tamoxifen. To this end, rats with small tumors induced by 1-methyl-1-nitrosourea (MNU) were treated with tamoxifen, radiation, or a combination of the two modalities.